Explore the vast range of titles available.

Monoclonal antibodies targeting the regulatory immune \"checkpoint\" receptors CTLA-4, PD-1, and PD-L1 are now standard therapy for diverse malignancies including melanoma, lung cancer, and renal cell carcinoma. Although effective in many patients and able to induce cures in some, targeting these regulatory pathways has led to a new class of immune-related adverse events. In many respects, these immune toxicities resemble idiopathic autoimmune diseases, such as inflammatory bowel disease, autoimmune hepatitis, rheumatoid arthritis, and vitiligo. Understanding the pathogenesis of these immune toxicities will have implications not only for care of patients receiving checkpoint blockade but may also provide critical insights into autoimmune disease. The gastrointestinal (GI) mucosa is arguably the most complex barrier in the body, host to a diverse commensal microflora and constantly challenged by ingested foreign proteins both of which must be tolerated. At the same time, the GI mucosa must defend against pathogenic microorganisms while maintaining sufficient permeability to absorb nutrients. For these reasons, regulatory cells and receptors are likely to play a central role in maintaining the gut barrier and GI toxicities, such as colitis and hepatitis are indeed among the most common side effects of CTLA-4 blockade and to a lesser extent blockade of PD-1 and PD-L1. High-dose corticosteroids are typically effective for management of both checkpoint colitis and hepatitis, although a fraction of patients will require additional immune suppression such as infliximab. Prompt recognition and treatment of these toxicities is essential to prevent more serious complications.

Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory \"checkpoint\" receptors CTLA-4, PD-1, or its ligand PD-L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases.

Purpose of Review Checkpoint inhibitor (CPI) immunotherapy has transformed the treatment of multiple cancers over the past decade, leading to durable remissions, but also to severe inflammatory toxicities. These toxicities, termed immune-related adverse events (irAEs), can affect any organ system in the body, but commonly induce inflammation in barrier organs. Gastrointestinal (GI) and hepatic irAEs are among the most frequent and most severe from contemporary immunotherapies, with inflammation in the colon and or small intestines (entero)colitis as the single most common GI irAE. The aim of this review is to describe the evidence supporting our current understanding of CPI enterocolitis and hepatitis, as well as the management of these entities. Recent Findings Although most patients who develop enterocolitis recover without long-term GI sequelae, enterocolitis is still an important reason for treatment discontinuation, which, in patients with metastatic cancer, can be a life-threatening outcome. At present, we have almost no prospective, randomized data regarding the management of CPI enterocolitis, and current management algorithms are based on expert opinion and small retrospective studies with a high likelihood of bias. Retrospective studies have defined colonic ulceration as a predictor of colitis responsiveness to corticosteroids, and have defined microscopic colitis as a subtype of CPI enterocolitis with a distinct treatment response. Corticosteroids appear to be effective for 60–70% of patients with CPI enterocolitis, with about a third of patients requiring escalation to a biologic agent such as infliximab or vedolizumab. Yet proper sequencing of these treatments to minimize risk and maximize treatment benefit has not been established, and we do not know how treatment of colitis influences cancer outcomes. Summary CPI enterocolitis and hepatitis are important causes of treatment interruption and discontinue, and significant morbidity in patients undergoing immunotherapy. As guidelines for diagnosis and management rely heavily on expert opinion, we have an urgent need for randomized and prospective trials that use both colitis and cancer outcomes to determine optimal management strategies.

Deciphering immune recognition is critical for understanding a broad range of diseases and for the development of effective vaccines and immunotherapies. Efforts to do so are limited by a lack of technologies capable of simultaneously capturing the complexity of adaptive immunoreceptor repertoires and the landscape of potential antigens. To address this, we present receptor–antigen pairing by targeted retroviruses, which combines viral pseudotyping and molecular engineering approaches to enable one-pot library-on-library interaction screens by displaying antigens on the surface of lentiviruses and encoding their identity in the viral genome. Antigen-specific viral infection of cell lines expressing human T or B cell receptors allows readout of both antigen and receptor identities via single-cell sequencing. The resulting system is modular, scalable and compatible with any cell type. These techniques provide a suite of tools for targeted viral entry, molecular engineering and interaction screens with broad potential applications. RAPTR, a lentivirus surface display-based library-on-library screening method to decipher antigen and immunoreceptor identities

Ipilimumab, a monoclonal antibody that recognizes cytotoxic T lymphocyte antigen (CTLA)-4, was the first approved “checkpoint”-blocking anticancer therapy. In mouse tumor models, the response to antibodies against CTLA-4 depends entirely on expression of the Fcγ receptor (FcγR), which may facilitate antibody-dependent cellular phagocytosis, but the contribution of simple CTLA-4 blockade remains unknown. To understand the role of CTLA-4 blockade in the complete absence of Fc-dependent functions, we developed H11, a high-affinity alpaca heavy chain-only antibody fragment (VHH) against CTLA-4. The VHH H11 lacks an Fc portion, binds monovalently to CTLA-4, and inhibits interactions between CTLA-4 and its ligand by occluding the ligand-binding motif on CTLA-4 as shown crystallographically. We used H11 to visualize CTLA-4 expression in vivo using whole-animal immuno-PET, finding that surface-accessible CTLA-4 is largely confined to the tumor microenvironment. Despite this, H11-mediated CTLA-4 blockade has minimal effects on antitumor responses. Installation of the murine IgG2a constant region on H11 dramatically enhances its antitumor response. Coadministration of the monovalent H11 VHH blocks the efficacy of a full-sized therapeutic antibody. We were thus able to demonstrate that CTLA-4–binding antibodies require an Fc domain for antitumor effect.

Despite formidable barriers to designing, implementing, and completing clinical trials in the midst of a pandemic, there are ways to ensure that the selected trials are structured to maximize the chance that the key research questions will be definitively answered.

CD47 is an antiphagocytic ligand broadly expressed on normal and malignant tissues that delivers an inhibitory signal through the receptor signal regulatory protein alpha (SIRPα). Inhibitors of the CD47–SIRPα interaction improve antitumor antibody responses by enhancing antibody-dependent cellular phagocytosis (ADCP) in xenograft models. Endogenous expression of CD47 on a variety of cell types, including erythrocytes, creates a formidable antigen sink that may limit the efficacy of CD47-targeting therapies. We generated a nanobody, A4, that blocks the CD47–SIRPα interaction. A4 synergizes with anti–PD-L1, but not anti-CTLA4, therapy in the syngeneic B16F10 melanoma model. Neither increased dosing nor half-life extension by fusion of A4 to IgG2a Fc (A4Fc) overcame the issue of an antigen sink or, in the case of A4Fc, systemic toxicity. Generation of a B16F10 cell line that secretes the A4 nanobody showed that an enhanced response to several immune therapies requires near-complete blockade of CD47 in the tumor microenvironment. Thus, strategies to localize CD47 blockade to tumors may be particularly valuable for immune therapy.

Programmed death ligand 1 (PD-L1) is expressed on a number of immune and cancer cells, where it can downregulate antitumor immune responses. Its expression has been linked to metabolic changes in these cells. Here we develop a radiolabeled camelid single-domain antibody (anti-PD-L1 VHH) to track PD-L1 expression by immuno-positron emission tomography (PET). PET-CT imaging shows a robust and specific PD-L1 signal in brown adipose tissue (BAT). We confirm expression of PD-L1 on brown adipocytes and demonstrate that signal intensity does not change in response to cold exposure or β-adrenergic activation. This is the first robust method of visualizing murine brown fat independent of its activation state. Current approaches to visualise brown adipose tissue (BAT) rely primarily on markers that reflect its metabolic activity. Here, the authors show that PD-L1 is expressed on brown adipocytes, does not change upon BAT activation, and that BAT volume in mice can be measured by PET-CT with a radiolabeled anti-PD-L1 antibody.

Therapeutic antitumor antibodies treat cancer by mobilizing both innate and adaptive immunity. CD47 is an antiphagocytic ligand exploited by tumor cells to blunt antibody effector functions by transmitting an inhibitory signal through its receptor signal regulatory protein alpha (SIRPα). Interference with the CD47–SIRPα interaction synergizes with tumor-specific monoclonal antibodies to eliminate human tumor xenografts by enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP), but synergy between CD47 blockade and ADCP has yet to be demonstrated in immunocompetent hosts. Here, we show that CD47 blockade alone or in combination with a tumor-specific antibody fails to generate antitumor immunity against syngeneic B16F10 tumors in mice. Durable tumor immunity required programmed death-ligand 1 (PD-L1) blockade in combination with an antitumor antibody, with incorporation of CD47 antagonism substantially improving response rates. Our results highlight an underappreciated contribution of the adaptive immune system to anti-CD47 adjuvant therapy and suggest that targeting both innate and adaptive immune checkpoints can potentiate the vaccinal effect of antitumor antibody therapy.

The Court of Justice has delivered an extensive body of caselaw concerning the obligation of domestic courts to provide effective judicial protection to claimants relying upon Community law rights - including such landmark judgments as Factortame and Francovich. This book offers a critical analysis of the Court’s fast-changing approach to national procedural autonomy,and explores the difficult conceptual framework underpinning the caselaw. The author demonstrates how Community intervention in the domestic systems of judicial protection cannot remain unaffected by wider debates about the evolving European integration project, in particular, the tension between uniformity and differentiation as competing values influencing the exercise of Community regulatory competence. Because of its emphasis on an ideal of uniformity which has become increasingly untenable within the contemporary Community legal order, much of the existing academic discourse about national remedies and procedural rules now seems ripe for reconsideration. It is argued that the Court’s jurisprudence on the decentralised enforcement of Treaty norms needs to be interpreted afresh, having regard to the recent growth of regulatory differentiation within the Community system. National Remedies Before the Court of Justice provides a challenging account of this crucial field of EU legal studies. It includes detailed discussion of issues such as Member State liability in damages, Community control over national limitation periods, and the principles governing state aid and competition law enforcement. This book is of value to academics and practitioners alike.